Blockade of programmed death-1 in young (New Zealand Black x New Zealand White)F1 mice promotes the suppressive capacity of CD4+ regulatory T cells protecting from lupus-like disease

• Published in: The Journal of immunology (1950) Vol. 190; no. 11; pp. 5402 - 5410
• Main Authors: Wong, Maida, La Cava, Antonio, Hahn, Bevra H
• Format: Journal Article
• Language: English
• Published: United States 01-06-2013
• Subjects: Adaptive Immunity; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - pharmacology; Autoantibodies - biosynthesis; CD4 Antigens - metabolism; Disease Progression; Female; Gene Expression Regulation - drug effects; Immune Tolerance - drug effects; Immune Tolerance - genetics; Interleukin-2 - genetics; Interleukin-2 - immunology; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukin-6 - immunology; Interleukin-6 - metabolism; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - prevention & control; Mice; Mice, Inbred NZB; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Signal Transduction; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1202382

Programmed death-1 (PD-1) usually acts as a negative signal for T cell activation, and its expression on CD8(+)Foxp3(+) T cells is required for their suppressive capacity. In this study, we show that PD-1 signaling is required for the maintenance of functional regulatory CD4(+)CD25(+)Foxp3(+) regulatory T cells (CD4(+) T(reg)) that can control autoimmunity in (New Zealand Black × New Zealand White)F1 lupus mice. PD-1 signaling induced resistance to apoptosis and prolonged the survival of CD4(+) T(reg). In vivo, the blockade of PD-1 with a neutralizing Ab reduced PD-1 expression on CD4(+) T(reg) (PD1(lo)CD4(+) T(reg)). PD1(lo)CD4(+) T(reg) had an increased ability to promote B cell apoptosis and to suppress CD4(+) Th as compared with CD4(+) T(reg) with elevated PD-1 expression (PD1(hi)CD4(+) T(reg)). When PD-1 expression on CD4(+) T(reg) was blocked in vitro, PD1(lo)CD4(+) T(reg) suppressed B cell production of IgG and anti-dsDNA Ab. Finally, in vitro studies showed that the suppressive capacity of CD4(+) T(reg) depended on PD-1 expression and that a fine-tuning of the expression of this molecule directly affected cell survival and immune suppression. These results indicate that PD-1 expression has multiple effects on different immune cells that directly contribute to a modulation of autoimmune responses.